Deafness, Autosomal Recessive 1a

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-1A (DFNB1A) is caused by homozygous or compound heterozygous mutation in the GJB2 gene (121011), which encodes the gap junction protein connexin-26 (CX26), on chromosome 13q12.

Autosomal dominant deafness-3A (DFNA3A; 601544) is an allelic disorder. See also DFNB1B (612645), which is caused by mutation in the GJB6 gene (604418) on chromosome 13q12.

Clinical Features

Scott et al. (1995) studied a highly inbred Bedouin family with autosomal recessive deafness. The family belonged to a tribe founded approximately 200 years ago by an Arab-Bedouin male who immigrated from Egypt to the southern region of what was then Palestine. He married a local woman and had 7 children, 5 of whom survived to adulthood. Consanguineous marriage had been the rule in the tribe since its third generation. The tribe was then in its seventh generation and consisted of some 3,000 people, all of whom resided in a single geographic area in Israel that is separated from other Bedouin communities. Birth rates within the tribe were high, and polygamy was common. Within the past generation there had been 80 individuals with congenital deafness; all of the affected individuals were descendants of 2 of the 5 adult sons of the founder. The deafness was profound prelingual neurosensory hearing loss with drastically elevated audiometric thresholds at all frequencies. All deaf individuals had an otherwise normal phenotype with the absence of external ear abnormalities, retinopathy, or renal defects, and all were of normal intelligence.

Cheng et al. (2005) noted that 4% of 777 unrelated children with hearing loss had medical records that listed an environmental cause for the deafness, and that 11% of those with an unknown etiology were found to have GJB2/GJB6 mutations. Otoacoustic emissions testing to detect functional outer hair cells identified 76 children (10%) with positive emissions, consistent with auditory neuropathy. Five of the patients with auditory neuropathy were homozygous or compound heterozygous for mutations in the GJB2 gene. Cheng et al. (2005) suggested that lack of functional gap junctions due to GJB2 mutations does not necessarily destroy all outer hair cell function.

In a survey by Dodson et al. (2011), 127 (54%) of 235 respondents with DFNB1 due to mutations in the GJB2 and/or GJB6 genes reported vestibular dysfunction, compared to 25 (41%) of 61 deaf controls without DFNB1 deafness (p less than 0.03). Most of the DFNB1 patients with vertigo had to lie down for it to subside, and 48% reported that vertigo interfered with activities of daily living. Vertigo was reported by significantly more cases with truncating than nontruncating mutations and was also associated with a family history of dizziness. Dodson et al. (2011) concluded that vestibular dysfunction is more common in DFNB1 deafness than previously recognized.

Schimmenti et al. (2008) enrolled 95 infants with hearing loss from whom both exons of Cx26 were sequenced and the Cx30 deletion was assayed in a study comparing infants with and without connexin-related hearing loss. Among the 82 infants who underwent newborn screening, 12 infants had passed; 3 had connexin-related hearing loss. There were no differences in newborn hearing screening pass rate, neonatal complication, or hearing loss severity between infants with and without connexin-related hearing loss. Schimmenti et al. (2008) pointed out that not all infants with connexin-related hearing loss will fail newborn hearing screening. Family history correlates significantly with connexin-related hearing loss.

Inheritance

Direct genetic evidence for the existence of at least 2 nonallelic, recessive, phenotypically indistinguishable forms of congenital deafness was provided by the rather frequent pedigrees of the type reported by Stevenson and Cheeseman (1956). In only 5 of 32 hereditary deaf by hereditary deaf matings were all children deaf. From this, the authors concluded that there are probably 6 separate loci for recessive congenital deafness, assuming that the mutant genes at each have a similar frequency. See comments of Slatis (1957).

Chung et al. (1959) also supported the notion of multiple recessive forms of congenital deafness.

Fraser (1964) estimated that half of severe childhood deafness was due to simple mendelian inheritance and that 87% of this group is autosomal recessive.

By ingenious mathematical analysis, Morton (1960) concluded that recessive inheritance is responsible for 68% of congenital deafness, that homozygosity at any one of 35 loci can result in this phenotype and that 16% of the normal population are carriers of a gene for congenital deafness. See also Morton (1991).

Muhlmann (1930) reported an instance in which 2 individuals with congenital deafness, clearly with autosomal recessive disease because in each case parents were consanguineous and a sib was also affected, married and produced only children with normal hearing.

Mengel et al. (1969) presented an instructive pedigree in which 2 congenitally deaf parents had all normal-hearing offspring. One parent came from a Mennonite group with numerous cases of congenital deafness in a recessive pattern. The other parent came from an Amish group which also contained several persons with apparently recessively inherited congenital deafness.

Majumder et al. (1989) studied the genetics of prelingual deafness in 133 nuclear families from 25 large pedigrees in India. Segregation analysis revealed a model for prelingual deafness suggestive of unlinked diallelic autosomal loci. Individuals were affected if and only if they were recessive homozygous at both loci.

In Israel, Brownstein et al. (1991) studied families in which both parents had congenital deafness. Among 111 such couples in which the deafness was possibly recessive and there was at least 1 child, there were 12 with only deaf children and 5 with both deaf and hearing children. The number of loci for recessive deafness in the whole group was estimated to be 8 or 9. Matings within the same Jewish group (Sephardi, Eastern, or Ashkenazi) gave an estimate of 6.7 loci, whereas interethnic matings gave an estimate of 22 loci. A conclusion of the study for genetic counseling was that deaf spouses from different ethnic groups have a smaller risk for deaf children than those from the same ethnic group.

Mapping

Guilford et al. (1994) performed linkage analyses using highly polymorphic microsatellite markers in 2 consanguineous families from Tunisia with profound prelingual deafness. A maximum 2-point lod score of 9.88 at theta = 0.01 was found with a marker on chromosome 13q (D13S175). Linkage was also observed with the pericentromeric 13q12 loci D13S115 and D13S143. (Guilford et al. (1994) referred to this disorder as nonsyndromic recessive deafness and used the gene symbol NSRD1.)

Chaib et al. (1994) studied a family of French origin with an autosomal dominant form of neurosensory deafness. The deafness was moderate to severe, had a prelingual onset, and affected predominantly the high frequencies. By linkage analysis, they mapped the disorder to chromosome 13q (multipoint maximum lod score of 4.66 at D13S175). The findings suggested that different mutations in the candidate gene could cause either dominant or recessive neurosensory deafness. This situation, with dominant and recessive forms of the same disorder depending on the nature of the specific mutations, has been observed in epidermolysis bullosa dystrophica due to mutations in the COL7A1 gene (120120), in retinitis pigmentosa due to mutations in the rhodopsin gene (RHO; 180380), and in myotonia congenita due to mutations in the CLCN1 gene (118425), to list only 3 examples.

From linkage studies in 18 New Zealand and 1 Australian nonconsanguineous kindreds with nonsyndromic presumed congenital sensorineural deafness and a pedigree structure consistent with autosomal recessive inheritance, Maw et al. (1995) found linkage to markers D13S175, D13S143, and D13S115 on chromosome 13. The finding suggested that the DFNB1 locus may make an important contribution to autosomal recessive neurosensory deafness in a Caucasian population. While there was no statistically significant evidence for heterogeneity at any of the 3 marker loci tested, 9 of the 19 families showed cosegregation of marker haplotypes with deafness. In these 9 families, phenotypic variation was observed both within sibships (in 4 families), which indicated that variable expressivity characterized some genotypes at the DFNB1 locus, and between generations (in 2 families), which suggested allelic heterogeneity.

Scott et al. (1995) showed that nonsyndromic autosomal recessive deafness in a highly inbred Bedouin family was linked to chromosome 13q12. In 1 of 27 families of Pakistani origin with nonsyndromic recessive deafness, Brown et al. (1996) found linkage to the DFNB1 locus on chromosome 13. Haplotype analysis of markers in the pericentromeric region of 13q suggested a recombination event that mapped DFNB1 proximal to the marker D13S175 and in the vicinity of D13S143. In an erratum, the authors noted that further analysis placed D13S143 distal to D13S175 rather than proximal, and therefore the locus DFNB1 was likely to be located proximal to D13S143, as suggested by Scott et al. (1995).

Gasparini et al. (1997) performed a genetic linkage study with 4 microsatellite markers linked to DFNB1 in a total of 48 independent Mediterranean families, of which 30 and 18 were of Italian and Spanish descent, respectively. They concluded that DFNB1 played a role in 79% of Mediterranean families with nonsyndromic neurosensory autosomal recessive deafness.

Molecular Genetics

Kelsell et al. (1997) identified a homozygous mutation in the GJB2 gene (121011.0002) in affected members of 3 families with autosomal recessive nonsyndromic sensorineural deafness linked to 13q11-q12 (Brown et al., 1996). By immunohistochemical staining, Kelsell et al. (1997) demonstrated that CX26 has a high level of expression in human cochlear cells.

Denoyelle et al. (1999) studied 140 children from 104 families with various degrees of sensorineural hearing loss. CX26 mutations were present in 43 (49%) of 88 families with prelingual deafness compared with none of the 16 families with postlingual forms of deafness. CX26-associated deafness varied from mild to profound, and was associated with sloping or flat audiometric curves and a radiologically normal inner ear. Hearing loss was not progressive in 11 of 16 cases tested, and variations in the severity of deafness between sibs were common. Denoyelle et al. (1999) suggested that an important element for genetic counseling is that the severity of hearing loss in DFNB1 is extremely variable and cannot be predicted, even within families.

Dahl et al. (2006) identified a homozygous mutation in the GJB2 gene (V37I; 121011.0023) in 4 (8.3%) of 48 Australian children with slight or mild sensorineural hearing loss. All 4 children were of Asian background, and SNP analysis suggested a common founder effect. All 4 children showed bilateral high-frequency sensorineural hearing loss, and 3 also had low-frequency hearing loss. Two additional children who were heterozygous for V37I had mild high-frequency loss maximal at 6kHz, and mild low-frequency loss, respectively. In all, 55 children with slight or mild hearing loss were identified in a screening of 6,240 Australian school children.

Tang et al. (2006) analyzed the GJB2 gene in 610 hearing-impaired individuals and 294 controls and identified causative mutations in 10.3% of cases, with equivocal results in 1.8% of cases due to the detection of unclassified, novel, or controversial coding sequence variations or of only a single recessive mutation in GJB2. Thirteen sequence variations were identified in controls, and complex genotypes were observed among Asian controls, 47% of whom carried 2 to 4 sequence variations in the coding region of the GJB2 gene.

Iossa et al. (2010) reported an Italian family in which an unaffected mother and 1 of her deaf sons were both heterozygous for an allele carrying 2 GJB2 mutations in cis: the dominant R75Q (121011.0026) and the recessive 35delG (121011.0005), whereas her other deaf son did not carry either of these mutations. The results suggested that the recessive mutation 'canceled out' the effect of the dominant mutation by causing a truncated protein before reaching residue 75. Iossa et al. (2010) suggested that deafness in the 2 sons was due to another genetic cause and highlighted the importance of the report for genetic counseling.

Deafness, Digenic, GJB2/GJB6

Del Castillo et al. (2002) noted that in many patients (10-42%) with autosomal recessive nonsyndromic deafness who were found to have a mutation in the GJB2 gene, the second mutation remained unidentified. They demonstrated that 22 of 33 unrelated such patients, 9 of whom had evidence of linkage to 13q12, were compound heterozygous for a mutation in the GJB2 gene (35delG; 121011.0005) and a deletion in the GJB6 gene (604418.0004). Two subjects were homozygous for the GJB6 mutation. In the Spanish population, the GJB6 deletion was the second most frequent mutation causing prelingual deafness. The authors concluded that mutations in the GJB2 and GJB6 gene can result in a monogenic or digenic pattern of inheritance of prelingual deafness. Del Castillo et al. (2002) reported the deletion as 342 kb, but Del Castillo et al. (2005) stated that more recent sequencing data indicated that the deletion is 309 kb.

Pallares-Ruiz et al. (2002) found a deletion in the GJB6 gene in trans in 4 of 6 deafness patients heterozygous for a GJB2 mutation, suggesting a digenic mode of inheritance.

In 4 unrelated Spanish patients with autosomal recessive nonsyndromic hearing impairment who were heterozygous for 1 GJB2 mutant allele and did not carry the GJB6 309-kb deletion, del Castillo et al. (2005) identified a GJB6 232-kb deletion, which they referred to as del(GJB6-D13S1854) (see 604418.0006). The deletion was subsequently found in DFNB1 patients in the United Kingdom, Brazil, and northern Italy; haplotype analysis revealed a common founder shared among chromosomes studied from Spain, the United Kingdom, and Italy.

In 255 French patients with a phenotype compatible with DFNB1, Feldmann et al. (2004) found that 32% had biallelic GJB2 mutations, and 6% were compound heterozygous for a GJB2 mutation and the GJB6 342-kb deletion. Profoundly deaf children were more likely to have the biallelic GJB2 or heterozygous GJB2/GJB6 mutations.

In a study of 777 unrelated children with hearing loss, Cheng et al. (2005) identified GJB2 or GJB6 mutations in 12%; among those with an affected sib, 20% had GJB2 or GJB6 mutations. Ten patients were compound heterozygous for mutations in the GJB2 and GJB6 genes.

In 324 probands with hearing loss and 280 controls, including 135 probands and 280 controls previously reported by Tang et al. (2006), Tang et al. (2008) screened for DNA sequence variations in GJB2 and for deletions in GJB6. The 232-kb GJB6 deletion was not found, and the 309-kb GJB6 deletion was found only once, in a patient of unknown ethnicity who was also heterozygous for a truncating mutation in GJB2. Tang et al. (2008) suggested that the 232- and 309-kb deletions in the GJB6 gene may not be common in all populations.

Deafness, Digenic, GJB2/GJB3

Liu et al. (2009) reported digenic inheritance of nonsyndromic deafness caused by mutations in the GJB2 and GJB3 (603324) genes. Three of 108 Chinese probands with autosomal recessive deafness and only 1 mutant GJB2 allele (e.g., 121011.0014) were found to be compound heterozygous with a GJB3 mutation (603324.0011; 603324.0012). The findings were consistent with digenic inheritance; the unaffected parents were heterozygous for 1 of the mutant alleles.

Reviews

Willems (2000) reviewed the genetic causes of nonsyndromic sensorineural hearing loss.

Petersen and Willems (2006) provided a detailed review of the molecular genetics of nonsyndromic autosomal recessive deafness.

Population Genetics

In Tunisia, Ben Arab et al. (1990) estimated the frequency of nonsyndromic autosomal recessive sensorineural deafness to be 7 per 10,000. Chaabani et al. (1995) studied 30 deaf couples in Tunisian and estimated that the number of loci for nonsyndromic autosomal recessive deafness in this population was 8.3.

Nance et al. (2000) proposed a hypothesis for the high frequency of DFNB1 in many large populations of the world, on the basis of an analysis of the proportion of noncomplementary marriages among the deaf during the 19th century, which suggested that the frequency of DFNB1 may have doubled in the United States during the past 200 years. These so-called noncomplementary marriages between individuals with the same type of recessive deafness are incapable of producing hearing offspring, and the square root of their frequency among deaf marriages provides an upper limit for the prevalence of the most common form of recessive deafness at that time. To explain the increase, they suggested that the combination of intense assortative mating and relaxed selection increased both the gene and the phenotype frequencies for DFNB1. The proposed model assumed that in previous millennia the genetic fitness of individuals with profound congenital deafness was very low and that genes for deafness were then in a mutational equilibrium. The introduction of sign language in Europe in the 17th to 18th centuries was a key event that dramatically improved the social and economic circumstances of the deaf, along with their genetic fitness. In many countries, schools for the deaf were established, contributing to the onset of intense linguistic homogamy, i.e., mate selection based on the ability to communicate in sign language.

In some large populations, connexin-26 deafness has been observed but at a much lower frequency. In Mongolia, for example, where there is only 1 residential school for the deaf, sign language was not introduced until 1995. Moreover, the fitness of the deaf is much lower than that of their hearing sibs, assortative mating is much less frequent than in the United States, and connexin mutations account for only 1.3% of all deafness (Pandya et al., 2001).

Nance and Kearsey (2004) showed by computer simulation that assortative mating, in fact, can accelerate dramatically the genetic response to relaxed selection. Along with the effects of gene drift and consanguinity, assortative mating also may have played a key role in the joint evolution and accelerated fixation of genes for speech after they first appeared in Homo sapiens 100,000 to 150,000 years ago.

In 156 unrelated congenitally deaf Czech patients, Seeman et al. (2004) tested for the presence of mutations in the coding sequence of the GJB2 gene. At least 1 pathogenic mutation was detected in 48.1% of patients. The 3 most common mutations were W24X (121011.0003), 35delG (121011.0005), and 313del14 (121011.0034); the authors stated that testing for only these 3 mutations would detect over 96% of all disease-causing mutations in GJB2 in this population. Testing for 35delG in 503 controls revealed a carrier frequency of 1:29.6 (3.4%) in the Czech Republic.

Alvarez et al. (2005) screened the GJB2 gene in 34 Spanish Romani (gypsy) families with autosomal recessive nonsyndromic hearing loss and found mutations in 50%. The predominant allele was W24X (121011.0003), accounting for 79% of DFNB1 alleles. Haplotype analysis suggested that a founder effect is responsible for the high prevalence of this mutation among Spanish gypsies. 35delG (121011.0005) was the second most common allele (17%).

Arnos et al. (2008) collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay (1898). Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children increased by a factor of more than 5 in the aforegoing 100 years. Additional analysis within their sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920-1980). Arnos et al. (2008) concluded that their data were consistent with the increase in the frequency of DFNB1 predicted by their previous simulation studies, and provided convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.

Schimmenti et al. (2008) enrolled 95 infants with hearing loss from whom both exons of Cx26 were sequenced and the Cx30 deletion was assayed in a study comparing infants with and without connexin-related hearing loss. Overall among these 95 patients, biallelic mutations were identified in 24.7%, but in only 9.1% of infants of Hispanic origin. Schimmenti et al. (2008) concluded that connexin-related hearing loss occurs in one quarter of infants in an ethnically diverse hearing loss population but with a lower prevalence in Hispanic infants.

Tekin et al. (2010) screened the GJB2 gene in 534 Mongolian probands with nonsyndromic sensorineural deafness and identified biallelic GJB2 mutations in 23 (4.5%) deaf probands. The most common mutation, IVS1+1G-A (121011.0029), appeared to have diverse origins based on multiple associated haplotypes. Tekin et al. (2010) stated that they found a lower frequency of assortative mating (37.5%) and decreased genetic fitness (62%) of the deaf in Mongolia compared to Western populations, which explained the lower frequency of GJB2 deafness in Mongolia.

Barashkov et al. (2011) found homozygosity for the IVS1+1G-A mutation in GJB2 in 70 of 86 patients from the Yakut population isolate in eastern Siberia with nonsyndromic hearing impairment. Six patients were compound heterozygous for this mutation and another pathogenic GJB2 mutation. Audiometric examination was performed on 40 patients who were homozygous for the mutation. Most (85%) had severe to profound hearing impairment, 14% had moderate impairment, and 1% had mild hearing loss. There was some variability in hearing thresholds. The carrier frequency for this mutation in this population was estimated to be 11.7%, the highest among 6 eastern Siberian populations analyzed, and the mutation was estimated to be about 800 years old. The findings were consistent with a founder effect, and Barashkov et al. (2011) postulated a central Asian origin for the mutation.

Among 15,799 ethnically diverse individuals screened for DFNB1 carrier status, Lazarin et al. (2013) identified 371 carriers (2.3%), for an estimated carrier frequency of approximately 1 in 43. Five 'carrier couples' were identified. Six individuals were identified as homozygotes or compound heterozygotes. Among 756 individuals of east Asian origin, the carrier frequency was 1 in 22.

In 6 Guatemalan probands with DFNB1A, Carranza et al. (2016) identified a homozygous truncating mutation in the GJB1 gene (W44X; 121011.0040). Two additional probands with deafness were compound heterozygous for the W44X mutation and another pathogenic mutation. The patients were from a cohort of 133 Guatemalan families with hearing loss who underwent sequencing of the GJB1 gene. The W44X mutation was the most common GJB1 pathogenic variant identified, accounting for 21 of 266 alleles, and 62% of the mutant GJB1 alleles identified. Haplotype analysis indicated a founder effect in this population, and ancestry analysis of individuals with this pathogenic variant showed a close match with Mayans. The W44X mutation always occurred with a benign c.79G-A variant (V27I) in the GJB1 gene.

History

In the pre-mendelian era, Meniere (1846, 1856) noted the role of parental consanguinity in deafness. Boudin (1862) noted the association between consanguinity and congenital deafness.

Groce (1985) traced the history of congenital deafness on Martha's Vineyard, the Massachusetts island. The first deaf person moved to the island in 1694. Groce (1985) estimated that in the 19th century 1 in 155 persons on the island was born deaf. Because there were deaf members in virtually every family in the western part of the island, everyone learned sign language, and the deaf were fully integrated into every aspect of life. Under these circumstances, deafness was not a disability or a handicap.

Mengel et al. (1967) found severe deafness in 16 members of a kindred. By history, all were born with at least some hearing but suffered progressive severe loss in later childhood. Sonographic and speech analysis gave further evidence of some hearing in early childhood. Audiologic tests suggested cochlear location of the defect. Although successive generations were affected in some instances, consanguinity and recessive inheritance were thought to account for the finding. Barr and Wedenberg (1964) described a similar disorder in 4 of 7 sibs.

Among the 11 children of consanguineous parents, Cremers (1979) observed 2 boys and a girl with progressive sensorineural deafness, first noticed at ages 4, 7 and 11 years. He found 2 reports of a similar deafness and concluded that it was different from the deafness reported by Mengel et al. (1967). A second family was reported by Cremers et al. (1987). Progressive sensorineural hearing loss started mainly in the higher frequencies. They also found an abrupt decline in the audiogram that slowly decreased with the increase of low frequency hearing loss.

Ormerod (1960) recognized the following types of congenital deafness, beginning with the most complete form: (1) Michel type--complete lack of development of internal ear. (2) Mondini-Alexander type--development only of a single curved tube representing the cochlea, and similar immaturity of the vestibular canals. (3) Bing-Siebenmann type--bony labyrinth well formed but membranous part and particularly the sense organ poorly developed. This type is often associated with retinitis pigmentosa. (4) Scheibe cochleosaccular type--In this form, which is the most frequent one, the vestibular part is developed and functioning. Malformation is restricted to the membranous cochlea and saccule. This type occurs in Waardenburg syndrome. (5) Siebenmann type--changes mainly in middle ear and often due to thyroid hormone deficiency. The middle ear is involved in myxomatous change which may be embryonic persistence. (6) Microtia and atresia of the meatus--abnormality limited to the external ear.